Evidence map›Paper›PMID 40340864›Full record

ArticleArthritis research & therapy2025

Smoking as a risk factor for rheumatoid arthritis: predominant association with IgA autoantibodies - comprehensive analysis of anti-modified protein antibodies with smoking and genetic risk factors in rheumatoid arthritis.

Tineke J van Wesemael, Fraser R Morton, Judith W Heutz, Marc P Maurits, Annemarie L Dorjée, Duncan Porter, Tom W J Huizinga, Karim Raza, Rene E M Toes, Rachel Knevel and 3 more

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Article in Arthritis research & therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Tineke J van WesemaelDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Fraser R MortonSchool of Infection and Immunity, University of Glasgow, University Avenue, Glasgow, G12 1QQ, UK.
Judith W HeutzDepartment of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands.
Marc P MauritsDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Annemarie L DorjéeDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Duncan PorterSchool of Infection and Immunity, University of Glasgow, University Avenue, Glasgow, G12 1QQ, UK.
Tom W J HuizingaDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Karim RazaRheumatology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Rene E M ToesDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Rachel KnevelDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands.
Pascal H P de JongDepartment of Rheumatology, Erasmus Medical Center, Rotterdam, The Netherlands.
Anna SvärdCenter for Clinical Research Dalarna, Uppsala University, Falun, Sweden.
Diane van der WoudeDepartment of Rheumatology, Leiden University Medical Center, Albinusdreef 2, Leiden, 233ZA, the Netherlands. dvanderwoude@lumc.nl.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundRheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of autoantibodies against modified proteins, known as anti-modified protein autoantibodies (AMPAs). While the relationship between different AMPA isotypes and various risk factors remains poorly understood, investigating this association is important for a deeper understanding of RA pathophysiology. Smoking, has its primary effects in the lungs, and it remains unclear whether smoking is preferentially linked to specific AMPA isotypes, such as IgA, which could suggest a mucosal origin. Therefore, we set out to investigate the association between smoking, genetic risk factors for RA, and the presence of specific AMPA isotypes, particular IgA.

methodsIn 618 RA patients, anti-citrullinated protein antibodies (ACPA-) and anti-acetylated protein antibodies (AAPA-) IgA, -IgG and -IgM and RF-IgA and -IgM were measured by ELISA. Associations with genetic risk factors, smoking and autoantibodies were assessed with logistic regression analysis. For replication, a comprehensive meta-analysis incorporating 3309 RA patients was performed.

resultsSmoking was primarily associated with IgA AMPA, with associations that prevailed after correcting for the concurrent presence of AMPA IgG (ACPA-IgA OR 1.89 [1.14-3.12], AAPA-IgA 2.30 [1.35-3.94]). To further substantiate these results, we performed a meta-analysis of 3309 RA patients and observed that smoking was again predominantly associated with the combined presence of ACPA-IgA in addition to ACPA-IgG (OR 2.05 [1.69-2.49], p < 0.001) versus the single presence of ACPA-IgG (OR 1.18 [0.97-1.44], p = 0.11). A gene-environment interaction between the most important genetic risk factor for RA (the HLA shared epitope alleles) and smoking was only seen in patients that were both ACPA-IgG and ACPA-IgA positive, but not in patients who were only positive for ACPA-IgG.

conclusionThese data provide a pivotal refinement of existing knowledge regarding risk factor associations for RA and lend novel support to the hypothesis that smoking may exert its effect on RA by the induction of local (auto)immune responses at mucosal sites.

Indexed as

Arthritis, RheumatoidAutoantibodiesImmunoglobulin ASmokingAdultAgedAnti-Citrullinated Protein AntibodiesFemaleGenetic Predisposition to DiseaseHumansMaleMiddle AgedRisk FactorsAnti-Citrullinated Protein AntibodiesAutoantibodiesImmunoglobulin AAnti-acetylated protein antibodiesAnti-citrullinated protein antibodiesAnti-modified protein antibodiesGenetic risk factorsRheumatoid arthritisSmoking

Identifiers

PMID40340864
PMCPMC12060357

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.